Highly oxygenated tetrahydropyrans and cyclohexanes are of interest as biochemical probes for disease related mechanisms, and, or drug leads for new therapeutic agents. These include unnatural analogs of carbohydrates that can act as glycomimetics, and natural products with potent activity. The broad long-term goal of this proposal is the development of synthetic methodology for such structures. We have shown that activation of 1-thio-1,2-0- isopropylideneacetals (TIA's) under mild conditions, lead to complex oxocarbenium ions, and this allows for novel approaches to highly oxygenated ring systems. In this project TIA chemistry will be applied to synthesis in three specific areas. We have prepared a novel C-disaccharide mimetic of sialyl Lewis X and determined its formational behavior and binding to P-selectin. Based on this information, the solution conformations of sLex, and the widely accepted model for selectin binding, we have proposed a bound conformation for this C-disaccharide. The first group of synthetic targets are a set of conformationally restrained analogs of this C-glycoside. These structures have been designed to investigate the optimal requirements for selectin binding. This information is relevant to the discovery of more potent, small molecule, selectin antagonists. The second target is a C-linked analog of myoinositol. This structure is a versatile precursor to a number of interesting mechanistic probes for interrogating the biosynthesis and function of phosphatidylinositol mannans (PIM's) in mycobacteria. This molecule therefore constitutes a valuable tool in drug development related to tuberculosis and other mycobacterial infections. the third target is an unnatural analog of the highly oxygenated natural product fumagillin. Derivatives of fumagillin have attracted attention as anti-angiogenic agents. Novel structures are in demand for drug optimization. This new analog has been designed to answer questions on drug specificity. The methods developed in this project promise to be of wider significance to other areas of carbohydrate recognition and synthesis.